Mannitol formulation for integrin receptor antagonist

ABSTRACT

Disclosed are pharmaceutical compositions of an integrin αvβ3 receptor antagonist containing mannitol as the binding agent. The compositions are prepared by wet granulation or direct compression tablet formulation. These pharmaceutical formulations are useful for inhibiting bone resorption associated with osteoporosis, metastatic bone disease, hypercalcemia of malignancy, and Paget&#39;s disease.

FIELD OF THE INVENTION

The present invention is directed to novel pharmaceutical compositionscontaining the integrin αvβ3 receptor antagonist3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)propionicacid, or a pharmaceutically acceptable salt thereof, methods ofpreparing such pharmaceutical compositions, and methods of inhibitingbone resorption and treating osteoporosis with such pharmaceuticalcompositions.

BACKGROUND OF THE INVENTION

The compound3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]imidazolidin-1-yl}-3(S)-(6-methoxypyridin-3-yl)propionicacid of structural formula I (Compound I), or a pharmaceuticallyacceptable salt thereof, is disclosed in U.S. Pat. No. 6,017,926 (Jan.25, 2000). Compound I is an antagonist of the integrin αvβ3 receptor andis useful for inhibiting bone resorption, restenosis, angiogenesis,diabetic retinopathy, macular degeneration, inflammatory arthritis,cancer, and metastatic tumor growth. It is particularly useful forinhibiting bone resorption associated with osteoporosis, metastatic bonedisease, hypercalcemia of malignancy, and Paget's disease.

Pharmaceutical compositions containing Compound I in the dosage form ofcompressed tablets can be prepared by either wet granulation or directcompression techniques. Tablets prepared by wet granulation usuallyrequire the addition of a diluent to form granules. The diluent whencontacted with water will swell or start to dissolve to form a gel-likeconsistency. The wet formulation process helps to form agglomerates ofpowders. These agglomerates are called “granules.” Typical diluentsinclude starch, starch paste, gelatin, and cellulosics, such ashydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose,hydroxypropylcellulose (HPC), and polyvinyl pyrrolidone (See,Remington's Pharmaceutical Sciences, 18^(th) ed., pp 1635-1636).Microcrystalline cellulose functions primarily as a bulking agent in wetgranulation formulations. The use of microcrystalline cellulose in wetgranulation or direct compression tablet formulations of Compound Iresults in physical instability of stressed tablets, such as tabletsexposed to elevated humidities and temperatures.

The present invention provides for pharmaceutical compositions ofCompound I prepared by wet granulation or direct compression withmannitol or a mannitol/microcrystalline cellulose mixture as thediluent. The use of mannitol or a mannitol/microcrystalline cellulosemixture in place of microcrystalline cellulose alone results in greaterphysical stability of coated and uncoated tablets containing Compound Ito elevated humidities and temperatures.

The present invention also provides a process to prepare pharmaceuticalcompositions of Compound I by wet granulation or direct compressionmethods using mannitol or a mannitol/microcrystalline cellulose mixtureas the diluent.

Another object of the present invention provides methods for inhibitingbone resorption and treating osteoporosis by administering to a host inneed of such treatment a therapeutically effective amount of one of themannitol-based pharmaceutical compositions of the present invention.

These and other objects will become readily apparent from the detaileddescription which follows.

DESCRIPTION OF THE INVENTION

One aspect of the present invention is directed to solid dosage forms,particularly tablets, for the medicinal administration of Compound I ora pharmaceutically acceptable salt thereof.

In a particular aspect of the present invention, the tablets comprise(a) Compound I, or a pharmaceutically acceptable salt thereof, as theactive pharmaceutical ingredient, (b) mannitol or amannitol/microcrystalline cellulose mixture as the diluent, (c) adisintegrant, and (d) a lubricant. In a class of this embodiment, thetablet may also contain a binding agent and/or an antioxidant. Finally,the tablet may be film-coated to provide additional stability to thedosage form, and a colorant, sweetening agent, and/or flavoring agentmay be added if desired.

Mannitol or a mixture of mannitol and microcrystalline cellulosefunctions as a diluent in the wet granulation or direct compressionmethod for the preparation of tablet formulations of Compound I.

The disintegrant may be one of several modified starches or modifiedcellulose polymers. In one embodiment, the disintegrant iscroscarmellose sodium. Croscarmellose sodium NF Type A is commerciallyavailable under the trade name “Ac-di-sol.”

Embodiments of lubricants include magnesium stearate, calcium stearate,stearic acid, surface active agents such as sodium lauryl sulfate,propylene glycol, sodium dodecanesulfonate, sodium oleate sulfonate, andsodium laurate mixed with stearates and talc, sodium stearyl fumarate,and other known lubricants. In one class of these embodiments, thelubricant is magnesium stearate.

The tablets of the present invention may optionally contain a bindingagent selected from the group consisting of hydroxypropylcellulose(HPC), hydroxypropylmethyl cellulose (HMPC), hydroxyethyl cellulose, andpolyvinyl pyrrolidone. One embodiment of such a binding agent ishydroxypropylcellulose.

An antioxidant may optionally be added to the formulation to impartchemical stability. The antioxidant is selected from the groupconsisting of α-tocopherol, γ-tocopherol, δ-tocopherol, extracts ofnatural origin rich in tocopherol, L-ascorbic acid and its sodium orcalcium salts, ascorbyl palmitate, propyl gallate, octyl gallate,dodecyl gallate, butylated hydroxytoluene (BHT), and butylatedhydroxyanisole (BHA). In one embodiment, the antioxidant is BHT or BHA.

Finally, the compressed tablets may be film-coated such as with amixture of hydroxypropylcellulose and hydroxypropylmethylcellulosecontaining titanium dioxide and/or other coloring agents, such as ironoxides, dyes, and lakes; a mixture of polyvinyl alcohol (PVA) andpolyethylene glycol (PEG) containing titanium dioxide and/or othercoloring agents, such as iron oxides, dyes, and lakes; or any othersuitable immediate-release film-coating agent(s).

Methods for the preparation of Compound I are disclosed in U.S. Pat. No.6,017,926 (Jan. 25, 2000), the contents of which are incorporated byreference in their entirety, and in WO 01/34602 (17 May 2001). Apharmaceutically acceptable salt of Compound I may also be employed inthe present invention.

In one embodiment the pharmaceutical compositions of the presentinvention are prepared by wet granulation methods and comprise about 25to 70% by weight of Compound I as the active ingredient; about 25 to 70%by weight of mannitol or a mixture of mannitol and microcrystallinecellulose; about 1 to 5% by weight of a disintegrant; about 0 to 5% byweight of a binding agent; and about 1 to 3% by weight of a lubricant.In a class of this embodiment the disintegrant is croscarmellose sodium,the binding agent is hydroxypropylcellulose, and the lubricant ismagnesium stearate. In a subclass of this class, the pharmaceuticalcompositions comprise about 33 to 67% by weight of Compound I as theactive ingredient; about 25-60% by weight of mannitol; about 1 to 4% byweight of croscarmellose sodium; about 1 to 4% by weight ofhydroxypropylcellulose; and about 1 to 2% by weight of magnesiumstearate. In a further subclass of this class of this embodiment thepharmaceutical compositions comprise about 33 to 67% by weight ofCompound I as the active ingredient; about 25-60% by weight of mannitol;about 3% by weight of croscarmellose sodium; about 3% by weight ofhydroxypropylcellulose; and about 2% by weight of magnesium stearate.

The pharmaceutical compositions may optionally comprise about 0 to 0.2%by weight of an antioxidant, such as BHT and BHA. In one embodiment thepharmaceutical composition comprises about 0.02% by weight of anantioxidant.

In another embodiment the pharmaceutical compositions of the presentinvention are prepared by direct compression methods and comprise about33 to 67% by weight of Compound I as the active pharmaceuticalingredient; about 25 to 60% by weight of mannitol; about 1 to 5% byweight of a disintegrant; about 0 to 20% by weight of microcrystallinecellulose; about 0 to 5% by weight of a binding agent; and about 1 to 3%by weight of a lubricant. In a class of this embodiment the disintegrantis croscarmellose sodium, the binding agent is hydroxypropylcellulose,and the lubricant is magnesium stearate. In a subclass of this class thepharmaceutical compositions comprise about 33 to 67% by weight ofCompound I as the active pharmaceutical ingredient; about 25 to 60% byweight of mannitol; about 3% by weight of croscarmellose sodium; about3% by weight of hydroxypropylcellulose; and about 2% by weight ofmagnesium stearate.

In another embodiment the pharmaceutical compositions are generally inthe form of compressed tablets. The tablets may be, for example, from 50mg to 800 mg net weight. In a class of this embodiment, the tablets maybe from 75 mg to 700 mg net weight. In a subclass of this class, thetablets may be from 100 mg to 600 mg net weight. The potency of theactive pharmaceutical ingredient (Compound I) in these tablets is about50 to 400 mg.

In a further embodiment of the present invention, the pharmaceuticalcompositions as envisioned for commercial development are as follows:

Tablets of 50 mg Potency Compound I (about 33% Drug Loading):

About 33% by weight of Compound I; about 40% by weight of mannitol;about 20% by weight of microcrystalline cellulose; about 3% by weight ofcroscarmellose sodium; about 2% by weight of magnesium stearate; about3% by weight of hydroxypropylcellulose (HPC); and optionally about 0.02%by weight of BHT or BHA. In the absence of microcrystalline cellulose,about 33% by weight of Compound I; about 60% by weight of mannitol;about 3% by weight of croscarmellose sodium; about 2% by weight ofmagnesium stearate; about 3% by weight of hydroxypropylcellulose (HPC);and optionally about 0.02% by weight of BHT or BHA.

Tablets of 50 mg Potency Compound I (about 50% Drug Loading):

About 50% by weight of Compound I; about 40% by weight of mannitol;about 3% by weight of croscarmellose sodium; about 2% by weight ofmagnesium stearate; about 3% by weight of hydroxypropylcellulose (HPC);and optionally about 0.03% by weight of BHT or BHA.

Tablets of 100 mg Potency of Compound I (about 67% Drug Loading):

About 67% by weight of Compound I; about 25% by weight of mannitol;about 3% by weight of croscarmellose sodium; about 2% by weight ofmagnesium stearate; about 3% by weight of hydroxypropylcellulose (HPC);and optionally about 0.02% by weight of BHT or BHA.

Tablets of 200 mg Potency Compound I (about 67% Drug Loading):

About 67% by weight of Compound I; about 25% by weight of mannitol;about 3% by weight of croscarmellose sodium; about 2% by weight ofmagnesium stearate; about 3% by weight of hydroxypropylcellulose (HPC);and optionally about 0.02% by weight of BHT or BHA.

Tablets of 400 mg Potency Compound I (about 67% Drug Loading):

About 67% by weight of Compound I; about 25% by weight of mannitol;about 3% by weight of croscarmellose sodium; about 2% by weight ofmagnesium stearate; about 3% by weight of hydroxypropylcellulose (HPC);and optionally about 0.02% by weight of BHT or BHA.

In one embodiment of the present invention, each of the tablets of thepotencies above is formulated in a 100 mg, 150 mg, 300 mg, or 600 mgtablet. The tablets are optionally film-coated with about 4% by weightof HPC/HPMC film-coat or about 4% by weight of polyvinyl alcohol(PVA)/polyethylene glycol (PEG) film-coat, each containing titaniumdioxide.

The pharmaceutical tablet compositions of the present invention may alsocontain one or more additional formulation ingredients selected from awide variety of excipients known in the pharmaceutical formulation art.According to the desired properties of the tablet, any number ofingredients may be selected, alone or in combination, based upon theirknown uses in preparing tablet compositions. Such ingredients include,but are not limited to, diluents, compression aids, disintegrants,lubricants, flavors, flavor enhancers, sweeteners, and preservatives.

The term “tablet” as used herein is intended to encompass compressedpharmaceutical dosage formulations of all shapes and sizes, whethercoated or uncoated. Substances which may be used for coating includehydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide,talc, sweeteners, colorants, and flavoring agents.

The tablet formulations of the present invention are prepared either bywet granulation or direct compression methods. The steps involved in thewet-granulation method comprise:

-   (1) adding Compound I, mannitol, microcrystalline cellulose    (optional), croscarmellose sodium, and hydroxypropyl cellulose to    the bowl of the granulator and dry mixing for a period of about 1    min to 3 min;-   (2) adding the appropriate granulating solution over a period of    about 2 to 5 min; for formulations containing BHA or BHT, the    granulating solution comprises about 15-18% ethanol: 85-82% water is    utilized; for formulations without BHA or BHT, an aqueous    granulating solution is used; a total of about 35-50% (w/w)    granulating solution is added to the batch;-   (3) wet massing for a period of about 0 to 5 min;-   (4) drying in an oven or fluid bed dryer to remove water; the oven    temperature is about 40° C. or the fluid bed dryer inlet temperature    is about 55° C. and the drying is performed for about 12 h for oven    drying or 0.5 to 1 h for fluid bed drying;-   (5) milling;-   (6) lubricating (such as with magnesium stearate);-   (7) compressing the lubricated granule mixture into a desired tablet    image; and, if desired,-   (8) film-coating.

Granulation is the process of adding the water to a powder mixture withmixing until granules are formed. The granulation step may be variedfrom 1 to 15 min, preferably 2 to 5 min. The lubrication step is theprocess of adding lubricant to the mixture; the lubrication step may bevaried from 1 to 15 min, preferably 2 to 5 min.

The steps involved in the direct compression method comprise:

-   (1) blending Compound I, mannitol, and croscarmellose sodium in a    V-blender or other suitable blender for a period of about 5 to 30    min;-   (2) optionally adding hydroxypropyl cellulose and/or    microcrystalline cellulose to improve compaction properties;-   (3) lubricating (such as with magnesium stearate) for about 1 to 15    min;-   (4) compressing the lubricated blend into a desired tablet image;    and, if desired,-   (5) film-coating.

An antioxidant, such as BHA or BHT, can be added by either layering itonto one of the excipients, preferably the mannitol, prior to blendingwith Compound I and the other excipients or by layering it onto CompoundI during the bulk drug synthesis process.

The present invention provides methods for inhibiting bone resorptionand treating osteoporosis by orally administering to a host in need ofsuch treatment a therapeutically effective amount of one of themannitol-based pharmaceutical compositions of the present invention. Inone embodiment the host in need of such treatment is a human. In anotherembodiment the pharmaceutical composition is in the dosage form of atablet.

The following examples further describe and demonstrate embodimentswithin the scope of the present invention. The examples are given solelyfor the purpose of illustration and are not intended to be construed aslimitations of the present invention as many variations thereof arepossible without departing from the spirit and scope of the invention.

EXAMPLE 1

100 mg Potency Tablet of Compound I (67% drug loading) - wet granulationCompound I* 101.1 mg Mannitol** 36.87 mg Hydroxypropyl cellulose 4.50 mgCroscarmellose sodium 4.50 mg Magnesium stearate 3.00 mg ButylatedHydroxyanisole (BHA) 0.03 mg*Equivalent to 100 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

The active pharmaceutical ingredient (Compound I), mannitol (Roquette35), croscarmellose sodium, and hydroxypropyl cellulose (Kucel EXF) weredry mixed using a high-shear granulator for 2 min. The granulatingsolvent (30 to 45% of a mixture of 82% purified water and 18% ethylalcohol, in which the BHA was dissolved) was added to this blend withthe high-shear granulator running over a 3 min period. The wetted masswas dried in a fluid-bed dryer at an inlet temperature of 55° C. for 0.5to 1 h. The dried material was then milled using a cone mill to achievefine granules. After milling, magnesium stearate (lubricant) was addedto the blend using a twin-shell blender for a period of 3 min. Thelubricated mixture was compressed using a rotary tablet press to providea 150.0 mg tablet containing 100 mg of active ingredient. The tablet wasoptionally film-coated with 6.00 mg of a standard HPC/HPMC/TiO₂film-coat formula to provide a 156.0 mg coated tablet. Any suitablecolorant, including lakes or dyes, may be added to the film coat toimpart the desired color, in the range of 0-1% tablet weight.

EXAMPLE 2

200 mg Potency Tablet of Compound I (67% drug loading) - wet granulationCompound I* 202.2 mg Mannitol** 73.74 mg Hydroxypropyl cellulose 9.00 mgCroscarmellose sodium 9.00 mg Magnesium stearate 6.00 mg ButylatedHydroxyanisole (BHA) 0.06 mg*Equivalent to 200 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using essentially the procedure of Example 1 toprovide a 300.0 mg tablet containing 200 mg of active ingredient. Thetablets were optionally coated with 12.00 mg of a standard HPC/HPMC/TiO₂film-coat formula (Opadry I®) to provide a 312.0 mg coated tablet.

EXAMPLE 3

400 mg Potency Tablet of Compound I (67% drug loading) - wet granulationCompound I* 404.4 mg Mannitol** 147.48 mg Hydroxypropyl cellulose 18.00mg Croscarmellose sodium 18.00 mg Magnesium stearate 12.00 mg ButylatedHydroxyanisole (BHA) 0.12 mg*Equivalent to 200 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using essentially the procedure of Example 1 toprovide a 600.0 mg tablet containing 400 mg of active ingredient. Thetablets were optionally coated with 24.00 mg of a standard HPC/HPMC/TiO₂film-coat formula (Opadry I®) to provide a 624.0 mg coated tablet.

EXAMPLE 4

50 mg Potency Tablet of Compound I (33% drug loading) - wet granulationCompound I* 51.00 mg Mannitol** 58.48 mg Microcrystalline Cellulose(Avicel) 29.24 mg Hydroxypropyl cellulose 4.50 mg Croscarmellose sodium4.50 mg Magnesium stearate 2.25 mg Butylated Hydroxyanisole (BHA) 0.030mg*Equivalent to 50 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using essentially the procedure of Example 1 toprovide a 150.0 mg tablet containing 50 mg of active ingredient. Thetablets were optionally coated with 6.00 mg of a standard HPC/HPMC/TiO₂film-coat formula (Opadry I®) to provide a 156.0 mg coated tablet.

EXAMPLE 5

50 mg Potency Tablet of Compound I (50% drug loading) - wet granulationCompound I* 51.07 mg Mannitol** 40.9 mg Hydroxypropyl cellulose 3.00 mgCroscarmellose sodium 3.00 mg Magnesium stearate 2.00 mg ButylatedHydroxyanisole (BHA) 0.030 mg*Equivalent to 50 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using essentially the procedure of Example 1 toprovide a 100.0 mg tablet containing 50 mg of active ingredient. Thetablets were optionally coated with 4.00 mg of a standard HPC/HPMC/TiO₂film-coat formula (Opadry I®) to provide a 104.0 mg coated tablet.

EXAMPLE 6

50 mg Potency Tablet of Compound I (33% drug loading) - wet granulationCompound I* 51.0 mg Mannitol** 86.22 mg Hydroxypropyl cellulose 4.50 mgCroscarmellose sodium 4.50 mg Magnesium stearate 3.75 mg ButylatedHydroxyanisole (BHA) 0.030 mg*Equivalent to 50 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using essentially the procedure of Example 1 toprovide a 150.0 mg tablet containing 50 mg of active ingredient. Thetablets were optionally coated with 6.00 mg of a standard HPC/HPMC/TiO₂film-coat formula (Opadry I®) to provide a 156.0 mg coated tablet.

EXAMPLE 7

50 mg Potency Tablet of Compound I (33% drug loading) - directcompression Compound I* 51.0 mg Mannitol** 90.75 mg Croscarmellosesodium 4.50 mg Magnesium stearate 3.75 mg*Equivalent to 50 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using the direct compression procedure describedabove to provide a 150.0 mg tablet containing 50 mg of activeingredient.

EXAMPLE 8

50 mg Potency Tablet of Compound I (33% drug loading) - directcompression Compound I* 51.0 mg Mannitol** 60.5 mg Microcrystallinecellulose 30.25 mg Croscarmellose sodium 4.50 mg Magnesium stearate 3.75mg*Equivalent to 50 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using the direct compression procedure describedabove to provide a 150.0 mg tablet containing 50 mg of activeingredient.

EXAMPLE 9

50 mg Potency Tablet of Compound I (50% drug loading) - directcompression Compound I* 51.0 mg Mannitol** 44 mg Croscarmellose sodium3.0 mg Magnesium stearate 2.0 mg*Equivalent to 50 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using the direct compression procedure describedabove to provide a 100.0 mg tablet containing 50 mg of activeingredient.

EXAMPLE 10

100 mg Potency Tablet of Compound I (67% drug loading) - directcompression Compound I* 101.1 mg Mannitol** 41.4 mg Croscarmellosesodium 4.50 mg Magnesium stearate 3.0 mg*Equivalent to 100 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using the direct compression procedure describedabove to provide a 150.0 mg tablet containing 100 mg of activeingredient.

EXAMPLE 11

200 mg Potency Tablet of Compound I (67% drug loading) - directcompression Compound I* 202.2 mg Mannitol** 82.8 mg Croscarmellosesodium 9.0 mg Magnesium stearate 6.0 mg*Equivalent to 200 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using the direct compression procedure describedabove to provide a 300.0 mg tablet containing 200 mg of activeingredient.

EXAMPLE 12

400 mg Potency Tablet of Compound I (67% drug loading) - directcompression Compound I* 404.4 mg Mannitol** 165.6 mg Croscarmellosesodium 18.0 mg Magnesium stearate 12.0 mg*Equivalent to 400 mg of the anhydrate.**Weight adjusted to account for water and impurities in the API.Method of Manufacture:

Tablets were prepared using the direct compression procedure describedabove to provide a 600.0 mg tablet containing 400 mg of activeingredient.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe casual variations, adaptations, modifications, deletions, oradditions of procedures and protocols described herein, as come withinthe scope of the following claims and equivalents.

1. A pharmaceutical composition comprising about 25 to 70% by weight ofthe active ingredient of structural formula I

or a pharmaceutically acceptable salt thereof; about 25 to 70% by weightof mannitol or about 25 to 70% by weight of a mixture of mannitol andmicrocrystalline cellulose; about 1 to 5% by weight of a disintegrant;about 0 to 5% by weight of a binding agent; and about 1 to 3% by weightof a lubricant.
 2. The pharmaceutical composition of claim 1 whereinsaid disintegrant is croscarmellose sodium, said binding agent ishydroxypropylcellulose, and said lubricant is magnesium stearate.
 3. Thepharmaceutical composition of claim 2 comprising about 33 to 67% byweight of said active ingredient; about 25 to 60% by weight of mannitol;about 1 to 4% by weight of croscarmellose sodium; about 1 to 4% byweight of hydroxypropylcellulose; and about 1 to 2% by weight ofmagnesium stearate.
 4. The pharmaceutical composition of claim 3comprising about 33 to 67% by weight of said active ingredient; about 25to 60% by weight of mannitol; about 3% by weight of croscarmellosesodium; about 3% by weight of hydroxypropylcellulose; and about 2% byweight of magnesium stearate.
 5. The pharmaceutical composition of claim1 additionally comprising about 0 to 0.2% by weight of an antioxidant.6. The pharmaceutical composition of claim 5 wherein said antioxidant isBHT or BHA.
 7. The pharmaceutical composition of claim 2 comprisingabout 33% by weight of said active ingredient; about 60% by weight ofmannitol; about 3% by weight of croscarmellose sodium; about 3% byweight of hydroxypropylcellulose; and about 2% by weight of magnesiumstearate.
 8. The pharmaceutical composition of claim 7 additionallycomprising about 0.02% by weight of BHT or BHA.
 9. The pharmaceuticalcomposition of claim 2 comprising about 33% by weight of said activeingredient; about 40% by weight of mannitol; about 20% by weight ofmicrocrystalline cellulose; about 3% by weight of croscarmellose sodium;about 3% by weight of hydroxypropylcellulose; and about 2% by weight ofmagnesium stearate.
 10. The pharmaceutical composition of claim 9additionally comprising about 0.02% by weight of BHT or BHA.
 11. Thepharmaceutical composition of claim 2 comprising about 50% by weight ofsaid active ingredient; about 40% by weight of mannitol; about 3% byweight of croscarmellose sodium; about 3% by weight ofhydroxypropylcellulose; and about 2% by weight of magnesium stearate.12. The pharmaceutical composiion of claim 11 additionally comprisingabout 0.02 to 0.03% by weight of BHT or BHA.
 13. The pharmaceuticalcomposition of claim 2 comprising about 67% by weight of said activeingredient; about 25% by weight of mannitol; about 3% by weight ofcroscarmellose sodium; about 3% by weight of hydroxypropylcellulose; andabout 2% by weight of magnesium stearate.
 14. The pharmaceuticalcomposition of claim 13 additionally comprising about 0.02% by weight ofBHT or BHA.
 15. The pharmaceutical composition of claim 1 prepared bywet granulation methods.
 16. A pharmaceutical composition comprisingabout 33 to 67% by weight of the active ingredient of structural formulaI

or a pharmaceutically acceptable salt thereof; about 25 to 60% by weightof mannitol; about 0 to 20% by weight of microcrystalline cellulose;about 1 to 5% by weight of a disintegrant; about 0 to 5% by weight of abinding agent; and about 1 to 3% by weight of a lubricant.
 17. Thepharmaceutical composition of claim 16 wherein said disintegrant iscroscarmellose sodium, said binding agent is hydroxypropylcellulose, andsaid lubricant is magnesium stearate.
 18. The pharmaceutical compositionof claim 17 comprising about 33 to 67% by weight of said activeingredient; about 25 to 60% by weight of mannitol; about 3% by weight ofcroscarmellose sodium; about 3% by weight of hydroxypropylcellulose; andabout 2% by weight of magnesium stearate.
 19. The pharmaceuticalcomposition of claim 16 prepared by direct compression methods.
 20. Amethod of inhibiting bone resorption in a human in need thereofcomprising orally administering to said human a boneresorption-inhibitory amount of the pharmaceutical composition ofclaim
 1. 21. A method of treating osteoporosis in a human in needthereof comprising orally administering to said human a therapeuticallyeffective amounnt of the pharmaceutical composition of claim
 1. 22. Thepharmaceutical composition of claim 1 further comprising one or moreagents selected from the group consisting of flavoring agents,colorants, and sweeteners.